1. Field of the Invention
The invention pertains to the field of pharmaceutical chemistry and provides a process for preparing 2,2-difluoroketene silyl acetals useful as pharmaceutical intermediates and a process for employing these acetals in the preparation of .alpha.,.alpha.-difluoro-.beta.-silyloxy-1,3-dioxolane-4-propanoic acid ester intermediates.
2. State of the Art
Ketene silyl acetals were first prepared by Petrov, et al.; see J. Gen. Chem. (USSR), 29, 2896-99 (1959). H. Greuter, et al., Tetrahedron Lett., 29 (27), 3291-94 (1988) teach the use of allylic esters of chlorodifluoroacetic acid in silicon induced Reformatsky-Claisen reactions in which 2,2-difluoroketene silyl acetals are the inferred intermediates. M. Yamana, et al., Tetrahedron Lett., 24 (5), 507-10 (1983) and Y. Takeuchi, et al., J. Chem. Soc. Perkin Trans. I, 1149-53 (1988) teach the preparation of difluoro silyl enol ethers on reaction of chlorodifluoromethyl ketones with zinc dust and trimethylsilyl chloride.
2,2-Difluoroketene silyl acetals have been prepared from the direct reaction of bromodifluoroacetate esters, zinc amalgam and chlorotrimethyl silane in triglyme; see J. C. Easdon, New Synthetic Methodology for Organofluorine Compounds, Ph.D. Thesis, Chemistry Department, Graduate College of the University of Iowa, July 1987. Kobayashi, et al. in Japanese Patent 2,067,250 and Tetrahedron Lett., 29 (15), 1803-06 (1988) describe the preparation of 2,2-difluoroketene silyl acetals by reacting methyl iododifluoroacetate with zinc dust in acetonitrile and treating the resultant organozinc species (Reformatsky reagent) with trialkylsilyl chloride. They further disclose the preparation of .alpha.,.alpha.-difluoro-2,2-dimethyl-.beta.-[(trialkylsilyl)oxy]-1,3-diox olane-4-propanoic acid methyl esters from the reaction of 2,3-O-isopropylidene-D-glyceraldehyde with the in situ-generated difluoroketene silyl acetals. The 2,2-difluoroketene silyl acetals proved to be superior to the corresponding Reformatsky reagents in that they afforded much higher erythro/threo (anti/syn) ratios in the condensation reaction with 2,3-O-isopropylidene glyceraldehyde than the latter reagents.
Matsumura, et al., in Japanese Patent 2,270,841, described the preparation of anti-.alpha.,.alpha.-difluoro-2,2-dimethyl-.beta.-[(trialkylsilyl)oxy]-1,3 -dioxolane-4-propanoic acid esters from the reaction of bromodifluoroacetate and iododifluoroacetate esters with trialkylsilyl chloride and zinc in acetonitrile, followed by treatment with 2,3-O-isopropylidene-D-glyceraldehyde and titanocene dichloride.
Esters of chlorodifluoroacetic acid are reported by R. W. Lang and B. Schaub, Tetrahedron Lett., 24, 2943-6 (1988) to undergo Reformatsky-type condensation reactions with aldehydes on treatment with activated zinc dust in dimethylformamide. However, low yields were obtained when they attempted to condense aliphatic, enolizable aldehydes with chlorodifluoro-acetate under these conditions, unless ultrasonication was used. S. Mcharek, et al., J. Organometallic Chem., 401, 211-15 (1991) similarly report Reformatsky-type condensation reactions of methyl chlorodifluoroacetate and simple aliphatic aldehydes in dimethylformamide, or mixtures of methylene chloride and dimethylformamide, by electrolytic reduction at a sacrificial zinc anode in the presence of a nickel catalyst. Note that the reaction of ethyl chlorodifluoroacetate with zinc dust and trialkylsilyl chloride in dimethylformamide does not afford the corresponding 2,2-difluoroketene silyl acetal, but rather yields the O-silylated carbinol amine formally derived from its condensation with the solvent; see R. W. Lang, Helv. Chim. Acta., 71, 369-73 (1988).
In addition to the utility described above, 2,2-difluoroketene acetals have proven useful as intermediates for preparing 3-amino-2,2-difluoro esters as described by T. Taguchi, et al., Tetrahedron Lett., 29, 5291-4 (1988). Similarly, Kitagawa, et al., Chem. Lett., 1307-10 (1990), have reported that 2,2-difluoroketene silyl acetals readily undergo Michael condensation with .alpha., .beta.-unsaturated carbonyl compounds or their derived acetals. These adducts have proven useful in the preparation of difluoro derivatives of the .alpha.-amino acids, glutamic acid and lysine. The .alpha.,.alpha.-difluoro-2,2-dimethyl-.beta.-[(trialkylsilyl)oxy]-1,3-diox olane-4-propanoic acid esters themselves are useful as intermediates in the preparation of antitumor and antiviral nucleosides.
An object of the present invention is to provide a process for preparing 2,2-difluoroketene silyl acetals from esters of chlorodifluoroacetate.
Another object of the invention is to provide a process for preparing .alpha.,.alpha.-difluoro-.beta.-silyloxy-1,3-dioxolane-4-propanoic acid esters using the 2,2-difluoroketene silyl acetals generated in situ.
Other objects and advantages of the invention will become apparent from the following description of embodiments.